MECHANISMS OF VIRUS-INDUCED ELASTIC ARTERITIS

我们已经开发了一种新的病毒诱导弹性动脉炎的小动物模型，这将使我们能够确定血管损伤的基本机制以及病毒感染和免疫系统在控制或促进慢性血管病理中的作用[自然医学，1997,3(12):1346-1353]。关于大弹性动脉炎症病变的机制知之甚少，血管炎的机制也不完全明确。近年来，疱疹病毒和活化淋巴细胞作为血管损伤的可能原因或辅助因素引起了人们的关注。尚未在可处理的模型系统中进行机制研究，以确定疱疹病毒感染和免疫系统如何相互作用以产生或控制血管病理。我们发现一种新发现的小鼠γ -疱疹病毒（gammaHV68）在正常小鼠中引起显著的弹性动脉炎，干扰素- γ (IFNgamma)无反应小鼠和B细胞缺陷小鼠比正常小鼠更容易被gammaHV68诱导动脉炎。进一步的分析表明：(1)gammaHV68对血管平滑肌细胞具有新的趋向性，(2)在动脉病变中发生了生产复制，(3)IFNgamma主要在细胞水平上起作用，(4)ifn无反应小鼠和B细胞缺陷小鼠的动脉病变病理明显不同。为了为分析病毒对慢性动脉炎的影响提供分子工具，我们对gammaHV68的基因组进行了测序（119,450 bp），证明gammaHV68与人类γ -疱疹病毒Epstein-Barr病毒和卡波西氏肉瘤疱疹病毒密切相关。我们最近分离了突变体和标记救援gammaHV68，并鉴定了候选的潜伏期相关gammaHV68基因。遗传工具的可用性分析宿主免疫反应和特定病毒基因的作用，将使我们能够定义gammaHV68诱导动脉炎的机制如下。目的1。确定潜伏性和生产性γ mahv68感染对慢性动脉炎的贡献。目标2。确定IFNgamma调节动脉炎的机制。目标3。确定B细胞调节动脉炎的机制。

We have developed a novel small animal model of virus induced elastic arteritis that will allow us to define fundamental mechanisms of vascular injury and the role of virus infection and the immune system in controlling or promoting chronic vascular pathology [Nature Medicine, 1997, 3(12):1346-1353]. Little is known about mechanisms that initiate inflammatory lesions of large elastic arteries, and the mechanisms underlying vasculitis are incompletely defined. Recently, attention has been paid to herpesviruses and activated lymphocytes as possible causes or cofactors in vascular injury. Mechanistic studies in a tractable model system have not been performed to determine how herpesvirus infection and the immune system interact to generate or control vascular pathology. We discovered that a newly characterized murine gamma-herpesvirus (gammaHV68) causes striking elastic arteritis in normal mice, and that interferon-gamma (IFNgamma) unresponsive mice and B cell deficient mice are much more susceptible than normal mice to induction of arteritis by gammaHV68. Further analysis revealed (i) a novel tropism of gammaHV68 for vascular smooth muscle cells, (ii) that productive replication is occurring in arteritic lesions, (iii) that IFNgamma acts primarily at the level of somatic cells, and (iv) the pathology of arteritic lesions in IFN-unresponsive and B cell deficient mice are strikingly different. To provide molecular tools for analysis of viral contributions to chronic arteritis we sequenced the genome of gammaHV68 (119,450 bp), demonstrating that gammaHV68 is closely related to the human gamma- herpesviruses Epstein-Barr virus and Kaposi's sarcoma herpesvirus. We have recently isolated mutant and marker rescue gammaHV68, and identified candidate latency-associated gammaHV68 genes. The availability of genetic tools for analysis of the host immune response arid the role of specific viral genes, will allow us to define mechanisms of gammaHV68 induced arteritis as follows. Aim 1. Determine the contribution of latent and productive gammaHV68 infection to chronic arteritis. Aim 2. Determine the mechanism by which IFNgamma regulates arteritis. Aim 3. Determine the mechanism by which B cells regulate arteritis.